Abstract - Angiotensin converting enzyme (ACE) is a peptidase that plays an important role in blood pressure control. Millions of patients take ACE inhibitors. The first data suggesting that ACE affects immune function were old studies documenting enhanced ACE production by the monocytic lineage cells comprising a granuloma. When genetic manipulation in mice is used to force over-expression of ACE in neutrophils or in monocytes and macrophages, these cells respond with a marked enhancement of immune function, as measured in both tumor and infection models. For example, mice over expressing ACE in neutrophils (NeuACE mice) have increased resistance to MRSA, and better in vitro killing of MRSA, P. aeruginosa, and K. pneumoniae. ACE over-expression increased neutrophil production of superoxide by NADPH oxidase following MRSA challenge, an effect independent of the angiotensin II AT1 receptor. These are very surprising and novel discoveries. The immune enhancement, a functional supercharging, is what makes this work significant. Our hypothesis is that over-expression of ACE alters the production or destruction of a peptide that has a remarkable developmental and metabolic effect on myelomonocytic cells. The potential payoff of this work is that, previous to our studies, there was nothing to suggest that ACE would have these immune effects. In other words, there is a physiologic pathway that is still not well understood, the regulation of which can achieve a marked enhancement of myelomonocytic cell function. Should we be able to identify how ACE affects the immune response, we will have discovered something very novel that could be manipulated to augment the immune response. We propose to study 1) where in the developmental lineage of myelomonocytic cells, ACE over-expression begins to affect the phenotype of the developing cells; 2) what are the metabolic effects of ACE over-expression and which of the two ACE catalytic domains is responsible for the metabolic and enhanced immune response seen in these cells. These data will be incorporated into a systematic analysis using mass spectrometry to try to determine the ACE substrate responsible for the enhanced immune response; and 3) how ACE over-expression leads to enhanced neutrophil activation of NADPH oxidase and thus better killing of pathogens. Such knowledge will identify a powerful but heretofore unknown means of regulating and enhancing the immune response.